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Gene therapy in Alzheimer's disease - potential for disease modification.

ABSTRACT: Alzheimer's disease (AD) is the major cause of dementia in the elderly, leading to memory loss and cognitive decline. The mechanism underlying onset of the disease has not been fully elucidated. However, characteristic pathological manifestations include extracellular accumulation and aggregation of the amyloid beta-peptide (Abeta) into plaques and intracellular accumulation and aggregation of hyperphosphorylated tau, forming neurofibrillary tangles. Despite extensive research worldwide, no disease modifying treatment is yet available. In this review, we focus on gene therapy as a potential treatment for AD, and summarize recent work in the field, ranging from proof-of-concept studies in animal models to clinical trials. The multifactorial causes of AD offer a variety of possible targets for gene therapy, including two neurotrophic growth factors, nerve growth factor and brain-derived neurotrophic factor, Abeta-degrading enzymes, such as neprilysin, endothelin-converting enzyme and cathepsin B, and AD associated apolipoprotein E. This review also discusses advantages and drawbacks of various rapidly developing virus-mediated gene delivery techniques for gene therapy. Finally, approaches aiming at down-regulating amyloid precursor protein (APP) and beta-site APP cleaving enzyme 1 levels by means of siRNA-mediated knockdown are briefly summarized. Overall, the prospects appear hopeful that gene therapy has the potential to be a disease modifying treatment for AD.

SUBMITTER: Nilsson P

PROVIDER: S-EPMC3823109 | biostudies-other | 2010 Apr

REPOSITORIES: biostudies-other

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Gene therapy in Alzheimer's disease - potential for disease modification.

Nilsson Per P Iwata Nobuhisa N Muramatsu Shin-ichi S Tjernberg Lars O LO Winblad Bengt B Saido Takaomi C TC

Journal of cellular and molecular medicine 20100216 4

Alzheimer's disease (AD) is the major cause of dementia in the elderly, leading to memory loss and cognitive decline. The mechanism underlying onset of the disease has not been fully elucidated. However, characteristic pathological manifestations include extracellular accumulation and aggregation of the amyloid beta-peptide (Abeta) into plaques and intracellular accumulation and aggregation of hyperphosphorylated tau, forming neurofibrillary tangles. Despite extensive research worldwide, no dise ...[more]

PMID: 20158567

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Project description:OBJECTIVE:Selective serotonin reuptake inhibitors (SSRIs) have increased cognitive performance in some clinical studies of Alzheimer's disease (AD), but it is has been difficult to dissociate whether this is due to direct effects on cognition (neurochemical or disease-modifying) or a secondary effect of mood stabilization. We performed a systematic review for preclinical and human clinical trial evidence to support the use of SSRIs specifically for the management of cognitive decline in AD. DATA SOURCES:(1) PUBMED without language restrictions from 1950s until 2004 and updated August 2006, terms: "serotonin uptake inhibitors"[MeSH] AND ("Alzheimer disease"[MeSH] OR "Cognition Disorders"[MeSH]) NOT "Parkinson disease"[MeSH] AND (Clinical Trial[ptyp] OR Letter[ptyp] OR Meta-Analysis[ptyp] OR Randomized Controlled Trial[ptyp]) AND "alzheimer disease" [MESH] OR "Alzheimer*" combined with AND to "ssri*" OR "serotonin reuptake inhibitors" [MESH] NOT Review[ptyp]. (2) Cochrane Database of Systematic Reviews, keywords "SSRI" and "Alzheimer's". STUDY SELECTION:The PubMed search yielded 57 hits. Of these, 23 were included in this review for their specificity to SSRI use in AD or indications on efficacy beyond depressive symptoms. The other 34 citations were excluded because: (1) depression or other mood or behavioral disturbance severity was the reported outcome measure, (2) effects of SSRIs on cognition were confounded by concomitant use of other drugs, (3) subjects described were young adults, and/or (4) subjects had traumatic brain injury. The Cochrane Database of Systematic Reviews, 3rd Quarter 2006, yielded six citations related to SSRIs. DATA EXTRACTION:Data extracted from clinical trials included name of SSRI tested, cognitive outcome measures, and adverse events reported, which could include cognitive worsening. DATA SYNTHESIS:Preclinical evidence for use of SSRIs to enhance cognition in AD includes an effect at the hippocampus through carbonic anhydrase activation or stimulation of hippocampal neurogenesis. The chemical structure of paroxetine, and not intrinsic SSRI activity, may also affect APP ectodomain expression to reduce amyloid plaque formation. Clinical trials in AD generally have not assessed cognitive outcomes independently from mood or behavior stabilization. Currently, clinical studies in AD only indirectly support the use of SSRIs for disease modification by confirming a serotonergic deficit during the course of illness. CONCLUSIONS:Lack of supportive evidence for SSRIs as cognition enhancers or disease modifiers in AD is the result of omissions in clinical trial design, as opposed to reporting of negative outcomes. The preclinical evidence warrants the study of SSRIs in AD using mood, behavior, cognition, neurochemistry, and possibly neuroimaging as outcome variables.

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Gene therapy in Alzheimer's disease - potential for disease modification.

Publications

Gene therapy in Alzheimer's disease - potential for disease modification.

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